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1. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Author

M. Schwinzer, Faisal Hammad Mekky Koua, Ashwin Chari, J. Lieske, Maria Garcia-Alai, Gleb Bourenkov, Russell J. Cox, Salah Awel, W. Ewert, Dušan Turk, Luca Gelisio, N. Werner, Hévila Brognaro, J. Pletzer-Zelgert, Juraj Knoska, Arwen R. Pearson, D. Melo, Matthias Rarey, Ilona Dunkel, Boris Krichel, Y. Gevorkov, A. Tolstikova, David von Stetten, Eike C. Schulz, Andrea Zaliani, Winfried Hinrichs, F. Trost, Helen M. Ginn, Xinyuanyuan Sun, Stephan Niebling, Holger Fleckenstein, Aleksandra Usenik, J. Wollenhaupt, Robin Schubert, Stephan Günther, Kristina Lorenzen, J. Boger, P. Reinke, Diana C. F. Monteiro, Bruno Alves Franca, Isabel Bento, Manfred S. Weiss, Ariana Peck, Dominik Oberthuer, Pedram Mehrabi, Pontus Fischer, Sebastian Günther, Jure Loboda, P. Lourdu Xavier, C. Schmidt, Christian Betzel, Huijong Han, N. Ullah, Philip Gribbon, Aida Rahmani Mashhour, Charlotte Uetrecht, Guillaume Pompidor, Christiane Ehrt, Christian G. Feiler, Saravanan Panneerselvam, Bernhard Ellinger, Christian M. Günther, Thomas J. Lane, Linlin Zhang, S. Meier, Tobias Beck, Henry N. Chapman, M. Domaracky, Sven Falke, Katarina Karničar, Markus Wolf, Cromarte Rogers, S. Saouane, Ivars Karpics, Rolf Hilgenfeld, Gisel E. Peña-Murillo, Vasundara Srinivasan, Alke Meents, Miriam Barthelmess, M. Galchenkova, B. Seychell, Beatriz Escudero-Pérez, Thomas A. White, Janine-Denise Kopicki, Joanna J. Zaitseva-Doyle, W. Brehm, M. Groessler, Brenna Norton-Baker, Frank Schlünzen, Chufeng Li, Henning Tidow, Maria Kuzikov, Andrea R. Beccari, Johanna Hakanpää, Henry Gieseler, Yaiza Fernández-García, Oleksandr Yefanov, Thomas R. Schneider, Anna Hänle, Jan Meyer, H. Andaleeb, V. Hennicke, and Publica

Subjects
0301 basic medicine, Drug, Peptidomimetic, media_common.quotation_subject, medicine.medical_treatment, Allosteric regulation, Life Sciences Building Blocks of Life Structure and Function, Drug Evaluation, Preclinical, 010402 general chemistry, medicine.disease_cause, Crystallography, X-Ray, Virus Replication, 01 natural sciences, Antiviral Agents, 03 medical and health sciences, Protein structure, Drug Development, Report, Catalytic Domain, Chlorocebus aethiops, medicine, Animals, Protease Inhibitors, Vero Cells, Coronavirus 3C Proteases, Coronavirus, media_common, Multidisciplinary, Protease, Chemistry, SARS-CoV-2, Biochem, Virology, 3. Good health, 0104 chemical sciences, 030104 developmental biology, Drug development, Viral replication, ddc:320, Medicine, ddc:500, Naturwissenschaften [500], Allosteric Site, Reports
Abstract

A large-scale screen to target SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is initially expressed as two large polyproteins. Its main protease, Mpro, is essential to yield functional viral proteins, making it a key drug target. Günther et al. used x-ray crystallography to screen more than 5000 compounds that are either approved drugs or drugs in clinical trials. The screen identified 37 compounds that bind to Mpro. High-resolution structures showed that most compounds bind at the active site but also revealed two allosteric sites where binding of a drug causes conformational changes that affect the active site. In cell-based assays, seven compounds had antiviral activity without toxicity. The most potent, calpeptin, binds covalently in the active site, whereas the second most potent, pelitinib, binds at an allosteric site. Science, this issue p. 642, A repurposed drug-library screen reveals two allosteric drug binding sites of the SARS-CoV-2 main protease., The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

Published
2021

2. Inhibition of SARS-CoV-2 main protease by allosteric drug-binding

Author

Henry Gieseler, David von Stetten, A. Tolstikova, Luca Gelisio, Yaiza Fernández-García, Guillaume Pompidor, Saravanan Panneerselvam, Cromarte Rogers, M. Galchenkova, Juraj Knoska, B. Seychell, Gleb Bourenkov, Ariana Peck, Stephan Niebling, D. Melo, Hévila Brognaro, Russell J. Cox, Rolf Hilgenfeld, W. Brehm, J. Lieske, Matthias Rarey, Aleksandra Usenik, Tobias Beck, Oleksandr Yefanov, Henry N. Chapman, Isabel Bento, C. Schmidt, M. Groessler, Ashwin Chari, Sven Falke, Katarina Karničar, Thomas J. Lane, Beatriz Escudero-Pérez, J. Boger, Bernhard Ellinger, Christian M. Günther, Christiane Ehrt, Markus Wolf, Jure Loboda, Thomas R. Schneider, Andrea Zaliani, P. Lourdu Xavier, Eike C. Schulz, J. Wollenhaupt, Brenna Norton-Baker, Ivars Karpics, Salah Awel, Aida Rahmani Mashhour, Frank Schlünzen, Chufeng Li, Henning Tidow, Robin Schubert, Y. Gevorkov, H. Andaleeb, P. Reinke, Stephan Günther, Christian G. Feiler, Manfred S. Weiss, Jo J. Zaitsev-Doyle, N. Ullah, M. Domaracky, Pontus Fischer, Linlin Zhang, Maria Kuzikov, V. Hennicke, W. Ewert, Faisal Hammad Mekky Koua, P. Gribbon, Xinyuanyuan Sun, Dominik Oberthuer, S. Meier, J. Pletzer-Zelgert, Kristina Lorenzen, Christian Betzel, M. Schwinzer, Bruno Alves Franca, Charlotte Uetrecht, S. Saouane, Pedram Mehrabi, Helen M. Ginn, Andrea R. Beccari, Johanna Hakanpää, Diana C. F. Monteiro, Ilona Dunkel, Janine-Denise Kopicki, Anna Hänle, Miriam Barthelmess, Jan Meyer, Dušan Turk, N. Werner, Thomas A. White, Boris Krichel, Winfried Hinrichs, F. Trost, Sebastian Günther, Filip Guicking, Vasundara Srinivasan, Alke Meents, Gisel E. Peña Murillo, Maria Marta Garcia Alai, Huijong Han, Arwen R. Pearson, and Holger Fleckenstein

Subjects
Drug, Protease, Peptidomimetic, Chemistry, medicine.medical_treatment, media_common.quotation_subject, Allosteric regulation, medicine.disease_cause, Virology, Virus, Drug development, Viral replication, medicine, media_common, Coronavirus
Abstract

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for the virus replication and, thus, a potent drug target. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

Published
2020

3. Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Author

Yaiza Fernández-García, Dominik Oberthuer, Christian Betzel, Tobias Beck, Markus Wolf, Kristina Lorenzen, M. Domaracky, Bruno Alves Franca, Jo J. Zaitsev-Doyle, Dušan Turk, Hévila Brognaro, Arwen R. Pearson, Henry N. Chapman, Jan Meyer, Robin Schubert, Stephan Günther, M. Galchenkova, Eike C. Schulz, B. Seychell, Manfred S. Weiss, H. Andaleeb, Aida Rahmani Mashhour, Y. Gevorkov, Sven Falke, Pedram Mehrabi, V. Hennicke, Beatriz Escudero-Pérez, Xinyuanyuan Sun, Juraj Knoska, Linlin Zhang, S. Meier, J. Pletzer-Zelgert, Holger Fleckenstein, N. Ullah, Rolf Hilgenfeld, Oleksandr Yefanov, Cromarte Rogers, Henry Gieseler, Thomas J. Lane, Ariana Peck, Alke Meents, C. Schmidt, J. Wollenhaupt, J. Lieske, Huijong Han, Helen M. Ginn, Bernhard Ellinger, Diana C. F. Monteiro, Christiane Ehrt, Pontus Fischer, Illona Dunkel, F. Trost, Luca Gelisio, Sebastian Günther, A. Tolstikova, Faisal Hammad Mekky Koua, Gisel Esperanza, D. Melo, Christian G. Feiler, Matthias Rarey, Andrea Zaliani, P. Reinke, M. Schwinzer, Russell J. Cox, Heshmat Noei, Salah Awel, N. Werner, Boris Krichel, Charlotte Uetrecht, Ashwin Chari, P. Gribbon, P. Lourdu Xavier, W. Brehm, S. Saouane, M. Groessler, Brenna Norton-Baker, Frank Schlünzen, Chufeng Li, Henning Tidow, Maria Kuzikov, Johanna Hakanpää, Miriam Barthelmess, Thomas A. White, and Filip Guicking

Subjects
Protease, biology, Chemistry, Stereochemistry, medicine.medical_treatment, Biophysics, Active site, Cleavage (embryo), Adduct, chemistry.chemical_compound, Covalent bond, Michael reaction, medicine, Tetralone, biology.protein, Moiety
Abstract

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.

Published
2020

4. LifeSoaks: a tool for analyzing solvent channels in protein crystals and obstacles for soaking experiments.

Author

Pletzer-Zelgert J, Ehrt C, Fender I, Griewel A, Flachsenberg F, Klebe G, and Rarey M

Subjects
Solvents, Proteins chemistry
Abstract

Due to the structural complexity of proteins, their corresponding crystal arrangements generally contain a significant amount of solvent-occupied space. These areas allow a certain degree of intracrystalline protein flexibility and mobility of solutes. Therefore, knowledge of the geometry of solvent-filled channels and cavities is essential whenever the dynamics inside a crystal are of interest. Especially in soaking experiments for structure-based drug design, ligands must be able to traverse the crystal solvent channels and reach the corresponding binding pockets. Unsuccessful screenings are sometimes attributed to the geometry of the crystal packing, but the underlying causes are often difficult to understand. This work presents LifeSoaks, a novel tool for analyzing and visualizing solvent channels in protein crystals. LifeSoaks uses a Voronoi diagram-based periodic channel representation which can be efficiently computed. The size and location of channel bottlenecks, which might hinder molecular diffusion, can be directly derived from this representation. This work presents the calculated bottleneck radii for all crystal structures in the PDB and the analysis of a new, hand-curated data set of structures obtained by soaking experiments. The results indicate that the consideration of bottleneck radii and the visual inspection of channels are beneficial for planning soaking experiments., (open access.)

Published
2023
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5. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease.

Author

Günther S, Reinke PYA, Fernández-García Y, Lieske J, Lane TJ, Ginn HM, Koua FHM, Ehrt C, Ewert W, Oberthuer D, Yefanov O, Meier S, Lorenzen K, Krichel B, Kopicki JD, Gelisio L, Brehm W, Dunkel I, Seychell B, Gieseler H, Norton-Baker B, Escudero-Pérez B, Domaracky M, Saouane S, Tolstikova A, White TA, Hänle A, Groessler M, Fleckenstein H, Trost F, Galchenkova M, Gevorkov Y, Li C, Awel S, Peck A, Barthelmess M, Schlünzen F, Lourdu Xavier P, Werner N, Andaleeb H, Ullah N, Falke S, Srinivasan V, França BA, Schwinzer M, Brognaro H, Rogers C, Melo D, Zaitseva-Kinneberg JI, Knoska J, Peña-Murillo GE, Mashhour AR, Hennicke V, Fischer P, Hakanpää J, Meyer J, Gribbon P, Ellinger B, Kuzikov M, Wolf M, Beccari AR, Bourenkov G, von Stetten D, Pompidor G, Bento I, Panneerselvam S, Karpics I, Schneider TR, Garcia-Alai MM, Niebling S, Günther C, Schmidt C, Schubert R, Han H, Boger J, Monteiro DCF, Zhang L, Sun X, Pletzer-Zelgert J, Wollenhaupt J, Feiler CG, Weiss MS, Schulz EC, Mehrabi P, Karničar K, Usenik A, Loboda J, Tidow H, Chari A, Hilgenfeld R, Uetrecht C, Cox R, Zaliani A, Beck T, Rarey M, Günther S, Turk D, Hinrichs W, Chapman HN, Pearson AR, Betzel C, and Meents A

Subjects
Animals, Antiviral Agents pharmacology, Chlorocebus aethiops, Crystallography, X-Ray, Drug Evaluation, Preclinical, Protease Inhibitors pharmacology, SARS-CoV-2 drug effects, Vero Cells, Virus Replication drug effects, Allosteric Site, Antiviral Agents chemistry, Catalytic Domain, Coronavirus 3C Proteases antagonists & inhibitors, Coronavirus 3C Proteases chemistry, Drug Development, Protease Inhibitors chemistry, SARS-CoV-2 enzymology
Abstract

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M pro ), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M pro In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2021
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